1

 

                 DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

                       FOOD AND DRUG ADMINISTRATION

 

               CENTER FOR FOOD SAFETY AND APPLIED NUTRITION

 

 

 

 

 

 

 

 

 

 

                     FOOD ADVISORY COMMITTEE MEETING

 

Advice on CFSAN'S Draft Report:

Approaches to Establish Thresholds for Major Food Allergens and for Gluten in Food

 

 

 

 

 

 

 

 

 

 

 

 

 

 

                         Thursday, July 14, 2005

 

                          8:30 A.M. to 5:20 P.M.

 

 

 

 

                            Greenbelt Marriott

                              6400 Ivy Lane

                              Grand Ballroom

                        Greenbelt, Maryland 20770

                                                                  2

 

                         P A R T I C I P A N T S

 

       FOOD ADVISORY COMMITTEE STANDING MEMBERS:

 

       Richard A. Durst, Ph.D. - Acting Chairman

       Jeffrey A. Barach, Ph.D. (Industry Representative)

       Patrick S. Callery, Ph.D.

       Dennis Gonsalves, Ph.D., M.S.

       Jean M. Halloran (Consumer Representative)

       Douglas C. Heimburger, M.D., M.S.

       Margaret C. McBride, M.D.

       Mark Nelson, Ph.D. (Industry Representative)

       Carol I. Waslien Ghazaii, Ph.D., R.D.

 

       TEMPORARY VOTING MEMBERS:

 

       Petr Bocek, M.D., Ph.D. (Absent 7/14/05 Session)

       Margaret Briley, Ph.D., R.D.

       Erica Brittain, Ph.D.

       Ciaran P. Kelly, M.D.

       Soheila June Maleki, Ph.D.

       David O. Oryang

       Marc D. Silverstein, M.D.

       Suzanne Teuber, M.D.

 

       FOOD AND DRUG ADMINISTRATION:

       Robert E. Brackett, Ph.D. - Director

       Food and Drug Administration, CFSAN

 

       Catherine Copp, J.D. - Senior Policy Advisor

       Food and Drug Administration, CFSAN

 

       Steven M. Gendel, Ph.D. - Senior Scientist

       Food and Drug Administration

       National Center for Food Safety and Technology

 

       Rhonda Kane, M.S., R.D. - Consumer Officer

       Food and Drug Administration, CFSAN

 

 Marcia Moore, Food Advisory Committee, Executive Secretary

                                                                  3

 

                   P A R T I C I P A N T S (Continued)

 

       FOOD AND DRUG ADMINISTRATION STAFF:

 

       Michael M. Landa, J.D. - Deputy Director for Regulatory Affairs

 Food and Drug Administration, CFSAN

 

 

       Stafano Luccioli, M.D. - Senior Medical Advisor

       Food and Drug Administration, CFSAN

 

       GUEST SPEAKERS:

 

       Pekka Collin, M.D., M.P.H. - Professor

       University of Tampere, Medical School, Finland

 

       Catherine L. Copp, J.D.

       Policy Advisor, CFSAN, FDA

 

       Alessio Fasano, M.D. - Professor of Pediatrics

       Medicine & Physiology and Director, the Mucosal

       Biology Research Center, Center for Celiac

       Research, University of Maryland School of

       Medicine

 

       Steven M. Gendel, Ph.D. - Senior Scientist

       National Center for Food Safety and Technology, FDA

 

       Rhonda R. Kane, M.S., R.D. - Consumer Safety

       Officer CFSAN, FDA

 

       Donald Kasarda, Ph.D. - Consultant and Retired

       Senior Scientist, Agriculture Research Service,

       USDA

 

       Cynthia Kupper, R.D., C.D. - Executive Director

       Gluten Intolerance Group of North America

 

       Joseph A. Murray, M.D. - Professor of Medicine

       The Mayo Clinic of Rochester, Minnesota

                                                                  4

 

                             C O N T E N T S

 

                                                               PAGE

       Call to Order and Welcome and Introductions

                 Richard Durst, Ph.D., Acting Chairman            6

 

       Use of Gluten Thresholds

                 Catherine L. Copp, J.D., CFSAN, FDA              9

 

       Introduction to Celiac Disease

                 Joseph Murray, M.D.                             11

 

       Patient Perspectives on Celiac Disease

                 Cynthia Kupper, R.D., C.D.                      69

 

       Grains

                 Donald Kasarda, Ph.D., USDA                     84

 

       Question and Answer Session                              108

 

       Prospective Studies

                 Alessio Fasano, M.D.                           114

 

       Question and Answer Session                              146

 

       Retrospective Studies

                 Pekka Collin, M.D., M.P.H.                     161

 

       Question and Answer Session                              182

 

       International Perspectives on Gluten-Free

                 Rhonda S. Kane, M.S., R.D., CFSAN, FDA         186

 

       Question and Answer Session                              198

 

       Public Comments:

 

                 Elaine Monarch                                 212

 

                 Alice Bast                                     220

 

                 Mary Schluckabeer                              225

 

                 Tom P. Sullivan                                232

 

                 Steve Taylor                                   240

                                                                  5

 

                             C O N T E N T S

 

                                                               PAGE

 

       Overview of Approaches to Establishing

         Thresholds: Gluten

                 Steven M. Gendel, Ph.D.                        253

 

       Question and Answer Session                              257

 

       Committee Discussion:

 

                 Panel Discussion with Guest Speakers           259

 

                 Gluten and Celiac Disease - FDA Questions      287

 

                 Revisit Food Allergens                         354

 

       Adjournment

                 Richard Durst, Ph.D., Acting Chairman          363

                                                                  6

 

                          P R O C E E D I N G S

 

               CALL TO ORDER AND WELCOME AND INTRODUCTIONS

 

                 CHAIRMAN DURST:  Good morning.  I would

 

       like to call the meeting to order.  All right, I

 

       would like to welcome everyone back and also

 

       welcome new participants in our meeting this

 

       morning.

 

                 For those of you who weren't here

 

       yesterday, there is a "Conflict of Interest

 

       Statement" over on the table, if you want to refer

 

       to that at all, otherwise I would also ask again

 

       that maybe our participants or our members of the

 

       Food Advisory Committee would introduce themselves

 

       again for the benefit of those who were not here

 

       yesterday.

 

                 I am Dick Durst, professor [of]chemistry at

 

       Food Science and Technology Department at Cornell

 

       University.

 

                 Marc, would you start it off?

 

                 DR. SILVERSTEIN:  Marc Silverstein, I'm a

 

       general internist and geriatrician at Baylor Health

 

       Care System in Dallas.

                                                                  7

 

                 DR. TEUBER:  Suzanne Teuber, I am an

 

       allergist at UC-Davis.

 

                 MR. ORYANG:  I am David Oryang.  I am a

 

       risk analyst and agricultural engineer at the

 

       United States Department of Agriculture, Animal and

 

       Plant Health Inspection Service.

 

                 DR. KELLY:  Good morning.  Ciaran Kelly, I

 

       am a gastroenterologist at Harvard Medical School

 

       in Boston.

 

                 DR. MALEKI:  I am Soheila Maleki.  I am a

 

       scientist with the USDA.

 

                 DR. BRITTAIN:  Erica Brittain, I am a

 

       statistician at the National Institute of Allergy

 

       and Infectious Disease.

 

                 DR. BRILEY:  Margaret Briley, University

 

       of Texas at Austin, nutritionist.

 

                 MRS. MOORE:  Marcia Moore, I am the

 

       executive secretary for the Food Advisory Committee

 

       and the Food and Drug Administration.

 

                 DR. WASLIEN:  I am Carol Waslien,

 

       nutritional epidemiologist at the School of

 

       Medicine, the University of Hawaii.

                                                                  8

 

                 DR. BRILEY:  I am Margaret McBride, child

 

       neurologist at Akron Children's Hospital.

 

                 DR. CALLERY:  Pat Callery, West Virginia

 

       University, pharmaceutical scientist.

 

                 DR. GONSALVES:  I am Dennis Gonsalves, a

 

       scientist at USDA.

 

                 DR. HEIMBURGER:  I am Doug Heimburger, a

 

       physician and nutrition specialist at the

 

       University of Alabama at Birmingham.

 

                 DR. BARACH:  Jeff Barach with Food

 

       Products Association here, in Washington, D.C., in

 

       regulatory affairs.

 

                 DR. NELSON:  Mark Nelson with the Grocery

 

       Manufacturers Association here, in Washington,

 

       D.C., and I am responsible for scientific and

 

       regulatory policy.

 

                 MS. HALLORAN:  Jean Halloran with

 

       Consumers Union located in Yonkers, New York, and I

 

       am director of food policy initiatives.

 

                 CHAIRMAN DURST:  Thank you very much.

 

                 I would also like to remind everyone and

 

       also for our new people here at the meeting that

                                                                  9

 

       the "Charge" of the Committee is written out on the

 

       meeting document.  The most important thing is that

 

       we are focusing on the "Threshold Working Group

 

       Draft Report on Approaches to Establish Thresholds

 

       for Major Food Allergens and for Gluten in Food."

 

                 We are not here to set any kind of

 

       thresholds or discuss the labeling of these foods

 

       for allergens, but strictly to make comments on the

 

       best approaches to use for setting these

 

       thresholds.

 

                 Did I cover everything that we need to?

 

                 (No verbal response.)

 

                 CHAIRMAN DURST:  In that case, let's begin

 

       with our first presentation.  This is

 

       Catherine Copp, the policy advisor for CFSAN, FDA,

 

       on the use of gluten thresholds.

 

                         USE OF GLUTEN THRESHOLDS

 

                 MS. COPP:  I have been asked this morning

 

       to proceed with discussion on gluten and threshold

 

       levels for gluten or possible thresholds for gluten

 

       framework.  It is similar to yesterday.  I simply

 

       want to provide you with some context for the

                                                                 10

 

       evaluating the Draft Report portion that addresses

 

       gluten in food.  This is the hazard of being first.

 

                 (Slide.)

 

                 MS. COPP:  Yesterday, I mentioned the Food

 

       Allergen Labeling and Consumer Protection Act.

 

       This is a new law that Congress passed last August.

 

       Although it focuses primarily on allergens, food

 

       allergens, Congress also directed FDA to address

 

       the separate problem of gluten in food.

 

                 When I say directed, I mean that Congress

 

       has mandated that the Agency consider and then

 

       establish regulations according to a schedule to

 

       define "gluten-free" for use on food labels and

 

       also to identify the appropriate use of the term.

 

                 As with Allergens, for consumers with

 

       celiac disease, strict avoidance of gluten at

 

       levels that will elicit an adverse effect is the

 

       only means to prevent potentially serious

 

       reactions.

 

                 Accurate, complete and informative

 

       labeling on foods can help these consumers achieve

 

       their goal.  We believe that understanding

                                                                 11

 

       thresholds for gluten and having a sound scientific

 

       framework for evaluating the existence of such

 

       thresholds will help FDA develop a definition of

 

       gluten-free and identify appropriate use of the

 

       term.  That's it.

 

                 Thank you.

 

                 CHAIRMAN DURST:  Does anyone have any

 

       comments or question on Catherine's presentation?

 

                 (No verbal response.)

 

                 CHAIRMAN DURST:  Okay.  We will move on

 

       then to the presentation from Dr. Joseph Murray,

 

       professor of medicine at the Mayo Clinic of

 

       Rochester, Minnesota, on the introduction to celiac

 

       disease.

 

                      INTRODUCTION TO CELIAC DISEASE

 

                 DR. MURRAY:  Good morning, Committee

 

       Members.  I will be providing a general overview to

 

       celiac disease.

 

                 (Slide.)

 

                 DR. MURRAY:  First of all, we will discuss

 

       what is celiac disease.  We will discuss, briefly,

 

       the pathogenesis of the disease; who gets it; what

                                                                 12

 

       the treatment is, at least in a very relatively

 

       superficial fashion.  We will discuss some of the

 

       complications and compliance issues of celiac

 

       disease and a prognosis or future of celiac

 

       disease.

 

                 (Slide.)

 

                 DR. MURRAY:  Obviously, yesterday was

 

       focused on food allergies.  "Celiac disease" is one

 

       of the food intolerances that is immune-mediated,

 

       though it is not thought to be IgE-mediated; so, it

 

       comes into the non-IgE-mediated food intolerances

 

       that are mediated by an immune response.

 

                 (Slide.)

 

                 DR. MURRAY:  Where does it happen?  It

 

       happens within the smaller intestine, predominantly

 

       the proximal, smaller intestine is the workhorse of

 

       the digestive system.  It is this surface of the

 

       intestinal lining that is maximally expanded by the

 

       development of circular folds and on top of these

 

       circular folds the so-called "villi," these villi,

 

       shown here in a histological picture, which

 

       maximize the digestive surface area.

                                                                 13

 

                 It is on the surface entrocytes of these

 

       villi that most of the enzymes and in the layer

 

       immediately above that in the lumen where most

 

       digestion of the macromolecules from nutrition are

 

       broken down and then absorbed.  This is just a

 

       picture.  It looks like one of those shag-ply

 

       carpets from the 1970s.  This is a normal

 

       appearance.

 

                 (Slide.)

 

                 DR. MURRAY:  However, celiac disease is an

 

       inflammatory state of the small intestinal mucosa.

 

       It occurs in those who are genetically predisposed,

 

       and it resolves, the damage resolves, with

 

       exclusion of dietary gluten.

 

                 Here, on the left, is a normal intestine

 

       with a normal villus structure; and on the right,

 

       fully evolved celiac disease with complete

 

       destruction.

 

                 The villi are gone, not only are they gone

 

       but this entire intestinal mucosa is greatly

 

       thickened and filled with inflammatory cells.  This

 

       is where the primary site of injury occurs in

                                                                 14

 

       celiac disease.

 

                 I didn't mention it, but it is a permanent

 

       condition.  While it will heal most of the time

 

       with exclusion of gluten, the intolerance to gluten

 

       is permanent and will recur when the individual is

 

       reexposed to gluten.

 

                 (Slide.)

 

                 DR. MURRAY:  Now, what causes celiac

 

       disease?

 

                 (Slide.)

 

                 DR. MURRAY:  We know there are two major

 

       components to this disease: the first is the

 

       genetic background of predisposition.

 

                 Much of that predisposition revolves in

 

       the HLA type, which is part of our human leucocyte

 

       antigen-recognition system.  It is how we determine

 

       self- and non-self and generate an immune response

 

       as appropriate and its interaction with

 

       environmental factors, primarily the environmental

 

       factor of gluten.

 

                 These two conspire together to produce an

 

       immune response that becomes out of control

                                                                 15

 

       resulting in inflammation, which we just showed to

 

       you, that occurs primarily in the proximal small

 

       intestine and then subsequently the consequences of

 

       this inflammation leading to malabsorption and

 

       symptoms.

 

                 (Slide.)

 

                 DR. MURRAY:  What do we know about the

 

       genetics of the disease?  For many years, we know

 

       there is a strong, familial predisposition to the

 

       disease.

 

                 If you are unlucky enough to be a

 

       monozygous twin of somebody affected with celiac

 

       disease, your concordance rate is 80 percent.  It

 

       is not 100 percent, but it is about 80 percent.  If

 

       you are a sibling of a celiac, your chance of

 

       having it is 10 percent.  If you are a child of,

 

       about 5 to 10 percent.

 

                 There is a very strong association with

 

       certain HLA molecules.  These are Class II MHC

 

       molecules but particularly two types.  First, DQ2

 

       is the predominant type that is required for celiac

 

       disease, and in some populations DQ2 is also an

                                                                 16

 

       enabling type.

 

                 These genes, however, while they are

 

       essentially required for the disease, are not

 

       sufficient alone to the development of the disease.

 

       Probably 30 to 40 percent of the Caucasian

 

       population carry one or both of these molecules,

 

       but most of them don't get celiac disease.  There

 

       are other HLA genes that are likely involved,

 

       though they have not been well elucidated and

 

       certainly not confirmed in many populations.

 

                 There are other chromosomal disorders --

 

       Down's syndrome, Turner's syndrome, and Williams

 

       syndrome -- that are associated with a greatly

 

       increased risk of developing celiac disease for

 

       reasons that are not entirely clear, but probably

 

       are associated with the increase risk of disease in

 

       those chromosomal disorders.

 

                 (Slide.)

 

                 DR. MURRAY:  Looking at the primary

 

       environmental trigger for the disease -- that is,

 

       gluten -- it is basically the storage proteins that

 

       come from these particular cultivated grasses:

                                                                 17

 

       wheat, barley, rye, and other similar grains from

 

       within those families.  Other grasses -- for

 

       example, rice, items such as corn, sorghum, millet,

 

       and probably not even oats -- are not involved in

 

       triggering the disease.

 

                 (Slide.)

 

                 DR. MURRAY:  It is the storage proteins

 

       from the endosperm compartment of the wheat kernel

 

       particularly, and those are gliadins oar glutenins

 

       that are thought to contain the antigenic moieties

 

       that trigger the disease.

 

                 (Slide.)

 

                 DR. MURRAY:  What is it about these wheat

 

       proteins?  Well, if you take wheat, as an example

 

 

       of the others, these storage proteins are uniquely

 

       high in certain amino acids, especially glutamines

 

       and prolines.

 

                 Over 30 percent of the amino acids in

 

       gliadin are glutamines.  The glutamines, of course,

 

       can be cross-linked to give the grain its

 

       resiliency.  Really the cooking ability, the

 

       ability to use wheat as such an effective way of

                                                                 18

 

       making things that stick together like bread, for

 

       example, and maintain their shape, is largely a

 

       property of these particular combinations of amino

 

       acids.

 

                 The proline sequences that contain or

 

       proline residues contained within the wheat

 

       proteins also appear to form helices, and these

 

       helices are resistant to digestion within the

 

       mammalian gut.

 

                 (Slide.)

 

                 DR. MURRAY:  This may be a key factor in

 

       what results in the likelihood of these peptides

 

       basically being maintained and becoming, then,

 

       still available for the immune system to recognize

 

       in a patient with celiac disease.

 

                 Now, gliadin molecules are presented by

 

       these HLA types to T-cells in the intestine, and

 

       T-cells that are specifically primed to respond to

 

       gluten.  There are certain gliadin molecules that

 

       have a higher affinity than others for these

 

       Class II molecules and then the T-cell receptor.

 

                 These peptides may be processed or altered

                                                                 19

 

       within the gut, perhaps, to make them more

 

       antigenic.  They may not start out very antigenic,

 

       but then they undergo some change within the gut

 

       that may make them more antigenic.

 

                 It turns out that some of these peptides

 

       that are particular immunodominant, these are the

 

       ones that are most likely to produce an immune

 

       response, that those immunodominant peptides may be

 

       digestion resistant because they contain those

 

       proline sequences that perform helix, making them

 

       relatively poorly digestible by peptidases within

 

       the gut.

 

                 (Slide.)

 

                 DR. MURRAY:  Now, it turns out that there

 

       is a contribution to this antigenic nature from

 

       within the intestine itself, and this may well be

 

       because of this enzyme tissue transglutaminase.

 

                 This is an enzyme that is present within

 

       the gut mucosa.  It is released by cells,

 

       especially fibroblasts when they become inflamed,

 

       and it cross-links cystine residues.

 

                 It turns out that it will also act on

                                                                 20

 

       gliadin by deamidating some of those glutamine

 

       residues, some specific glutamine residues, to

 

       glutamates, making it more antigenic by deamidating

 

       that gliadin peptide and making it fit more

 

       perfectly or with a tighter affinity into the

 

       binding groove of the DQ2-HLA molecule, and, hence,

 

       producing a more vigorous immune response within

 

       the gut.

 

                 (Slide.)

 

                 DR. MURRAY:  This is a schema, a

 

       relatively simplified schema, of what I have just

 

       talked about.  We start with wheat.  You look at

 

       particularly the ethanol-soluble fraction, and

 

       gliadin is probably broken up into smaller

 

       peptides, but still of a sufficient size to produce

 

       an immune response.

 

                 It is taken up across the epithelium

 

       presented by antigen presenting cells to the

 

       T-cells.  These are T-cells that will specifically

 

       respond to gluten then producing two types of

 

       responses: a cellular response, characterized by

 

       lymphocytes producing interferon gamma and possibly

                                                                 21

 

       other cytokines.  It is probably the cellular

 

       response that leads to the "inflammatory cascade"

 

       that produces the damaged epithelium characteristic

 

       of celiac disease.

 

                 It also produces help to the B-cell side,

 

       to produce plasma cells that produce antibodies.

 

       These antibodies are directed both against the

 

       exogenous antigen gliadin and also antibodies

 

       against tissue transglutaminase or what was known

 

       as an the endomysial antibody.  It is not known

 

       what the actual pathogenic role of this is, but it

 

       is a very useful serologic or blood marker for the

 

       disease.

 

                 I mentioned about the antigen getting

 

       changed by tissue transglutaminase.  This is a

 

       little cartoon which shows the peptide derived from

 

       gluten.  If you change one specific glutamine to a

 

       glutamic acid, which could be done by tissue

 

       transglutaminase, this then binds much more

 

       tightly.  This is the HLA molecule here on the

 

       surface of the antigen presenting cell, and it fits

 

       more perfectly into the T-cell receptor, producing

                                                                 22

 

       a more potent T-cell response.

 

                 (Slide.)

 

                 DR. MURRAY:  Now, there are other things

 

       that happen in the setting of celiac disease, and I

 

       am really touching just on the surface of many of

 

       these, but there are other things that result in

 

       this inflammation that damage the lining of the

 

       intestine.

 

                 For example, there are metallic proteases

 

       that damage the structural elements that maintain

 

       the structure that maintain villus structure.

 

       There is endothelial injury that occurs affecting

 

       the blood vessels in the villus.  There are

 

       antibodies, autoantibodies, that are produced that

 

       affect actin that are involved in the site

 

       maintaining the structure of the entrocyte itself.

 

                 (Slide.)

 

                 DR. MURRAY:  Recently, there has been work

 

       suggesting that there is a molecule called

 

       "zonulin" that may be released in the setting of

 

       celiac disease.

 

                 This is important because it opens up

                                                                 23

 

       tight junctions between entrocytes which may allow

 

       even more ready access of the antigen, the foreign

 

       antigens, between the cells into lamina propria

 

       where antigen-presenting cells can then present

 

       those peptides to the gluten-responsive T-cells,

 

       further accelerating the disease.

 

                 (Slide.)

 

                 DR. MURRAY:  Now, I pointed out that many

 

       people, 30 percent or more of the Caucasian

 

       population, carry DQ2 or DQ8.  Virtually, the

 

       entire population are exposed to gluten, but most

 

       people don't get the disease.

 

                 There must be triggers that produce the

 

       disease.  There is evidence that suggests that

 

       gluten in the infant diet, specifically the age of

 

       introduction of gluten into the infant's diet, may

 

       be important in triggering or at least producing

 

       autoantibody markers suggestive of celiac disease

 

       early in life.

 

                 It is not clear, however, if that changes,

 

       whether you delay introduction or not whether that

 

       changes, the lifetime risk of celiac disease, but

                                                                 24

 

       it certainly seems to be important in triggering or

 

       producing evidence in childhood at least of celiac

 

       disease immune markers.

 

                 The amount of gluten in the child's diet

 

       may be important.  There are other events such as

 

       pregnancy, infection, or surgeries that may bring

 

       previously asymptomatic celiac disease to clinical

 

       presentation.

 

                 (Slide.)

 

                 DR. MURRAY:  One could speculate, and I

 

       think this is based on some data, putting data

 

       together, that one's risk for celiac disease starts

 

       with your HLA type.  Only those who carry HLA types

 

       are at risk.  You, then, are exposed to gluten.

 

       Perhaps the timing of exposure is important,

 

       developing in some individuals a sensitivity to

 

       gluten.

 

                 Then, with the interaction of other

 

       factors such as other genes other than HLA, other

 

       things that may predispose one to autoimmunity

 

       including gender and other events that may occur --

 

       gastroenteritis, aging, postsurgical or postpartum

                                                                 25

 

       changes in the immune system that may occur -- may

 

       lead to a loss of tolerance, inflammation, and

 

       subsequent malabsorption.

 

                 (Slide.

 

                 DR. MURRAY:  Don Kasarda, who is here once

 

       used the term or suggested that celiac disease was

 

       a collision between our evolution of our immune

 

       system and our ability to recognize self and

 

       non-self through the HLA system and our cultivation

 

       of wheat and these other grasses.  This collision

 

       occurs in the intestine.

 

                 (Slide.)

 

                 DR. MURRAY:  Now, when this collision

 

       occurs and results in damage, how does it present?

 

       And who gets the disease?

 

                 (Slide.)

 

                 DR. MURRAY:  Well, this is classic celiac

 

       disease, and this is the way that I certainly

 

       learned about celiac disease.  A severe

 

       malnourished child with evidence of malnutrition

 

       often associated with the large, swollen abdomen

 

       but great muscle, terrific muscle, wasting and

                                                                 26

 

       protein-calorie malnutrition with symptoms that

 

       would occur sometime after the onset of gluten

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